Monoclonal antibody (mab) products are currently a fast

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1 Antibody Monoclonal Therapeutics Janice M. Reichert, Ph.D. Monoclonal antibody (mab) products are currently a fast growing category of drugs. Like antibodies produced naturally by the human immune system, mabs bind to specific targets and can engage the normal biological responses of the immune system. In the case of mabs, the result of the interactions can be directed by the design of the mab. With current technology, mabs can be made to perform various functions, including the elimination of tumor cells or infectious agents. The first method for producing mabs from specialized mouse cells was developed in the 1970s. By the 1980s, mab drugs for diseases such as cancer were studied in patients. Many of the early mouse-derived mabs did not perform well in patients, at least partly because the mouse protein was destroyed by the human immune system. New methods for production of human mab candidates were developed in the late 1980s and early 1990s. The improved versions (called chimeric, humanized or human mabs) have proven to be safe as well as effective. Today, 24 mab products are marketed in countries around the world (Table 1). Since 1990, more than 360 mabs have entered clinical study sponsored by commercial firms. Most of these mabs were developed for one of three categories of disease (Fig. 1): 56% were developed as anti-cancer agents, 24% were studied as treatments 408 APBN Vol. 11 No

2 for disorders of the immune system, and 10% were in studies as anti-infective drugs. The rest (10%) were intended as treatments for a variety of other illnesses, such as degeneration of the eye and disorders of the blood. More than 180 mab candidates are in clinical studies now. Conventional full-size mab drugs are large and complex molecules when compared to traditional small molecule drugs, but companies have recently developed methods to make smaller, less complex versions that retain desired functions. Full-size mab drugs are made of multiple chains of proteins bound together, but drugs made from fragments of these chains can be designed. These technologies yield various types of alternative mabs such as domain antibodies (developed by Domantis) and small modular immunopharmaceuticals (SMIPs, developed by Trubion). Therapeutic Areas Many pharmaceutical and biotechnology companies are interested in developing cancer treatments. Cancer is not a single disease, and so many new drugs are needed to treat different types of cancers. There are currently over 500 anticancer agents in clinical study. While just over 50% of these are traditional small molecule drugs, more than 100 candidates (20%) are mabs; the remainder of the anticancer agents are recombinant or natural proteins, oligonucleotides, synthetic peptides or natural products (7% or less of total for each). Companies are interested in developing anticancer mabs because they have higher approval success rates compared with all anticancer agents. Only about 5% of all cancer drugs that enter clinical study will be approved. In contrast, the approval success rate for chimeric and humanized anticancer mabs is about 20%. As anticancer agents, mabs have been thought of as magic bullets that can bind specifically to designated targets and destroy them either directly or indirectly. In designing anticancer drugs, the versatility of mabs is an advantage mabs can made to bind targets on the surface of tumor cells or to targets that are in body fluids (soluble targets) and they can carry destructive agents such as toxins or radioactive elements or use natural biological mechanisms such as activation of the immune system or blockage of cell signals to affect tumor cells. There are currently 11 anticancer mabs marketed worldwide. Three of these products have markets of over US$1 billion. The immunological diseases comprise a second important category of mab study. This category includes disorders of the immune system, such as rheumatoid arthritis, Crohn s disease, APBN Vol. 11 No

3 multiple sclerosis, as well as graft versus host disease and transplant rejection. mab studied for immunological diseases commonly block unwanted cellular signals generated by biological messengers such as the interleukin. This family of proteins has been targeted by about 25% of immunological mabs studied in the clinic since Currently, 10 immunological mabs are on the market in various countries and one other is in regulatory review in the US. The ability of mabs to bind specific targets and engage the human immune system makes them well suited for the prevention or treatment of infectious diseases. Indeed, mabs have also been studied as agents for the prevention or treatment of a limited number of viral and bacterial infections. mab treatments are given through a needle into veins or muscle, and so are not as convenient for the patient to take as oral antibiotics. They are also commonly more expensive than either antibiotics or vaccines. As a consequence, commercial anti-infective mab development has focused on viral and bacterial diseases that do not have effective conventional treatments or vaccines. These diseases include human immunodeficiency virus, respiratory syncytial virus (RSV), or hepatitis C virus infections. One mab is currently marketed for the prevention of RSV infection and nearly 20 mab candidates are now in clinical study for the treatment or prevention of a variety of infectious diseases. Clinical Study and US FDA Approval The time required for clinical study and regulatory approval for drugs can be lengthy, so it is important for companies to allow at least eight years for these two periods combined. Using the 21 US Food and Drug Administration (FDA)-approved products as the standard, the average time for clinical study and US FDA approval was about eight years. There were large variations in the actual phase lengths though. For example, the ranges for the anticancer mabs were remarkably broad 4.2 years to 11.7 years for the clinical time and 4.7 to 33.4 months for the approval time. The typical anticancer mab had an average clinical time of six years and a US FDA approval time of 6.2 months. On the average, the immunological mabs were in clinical study about the same length of time (6.4 years), but took twice as long for US FDA approval (12.7 months). The US FDA has special programs for assistance in the clinical study period, with a focus on treatments for diseases affecting limited numbers of people (orphan drug program) and for serious diseases such as cancer (fast track program). Companies developing drugs that might qualify for these programs should contact the US FDA for additional information about the benefits, which include assistance 410 APBN Vol. 11 No

4 with clinical study design. Discussions with US FDA should start before candidate drugs are given to humans. Of the mabs that are currently in clinical study, 22% have US orphan drug designation and 10% have US FDA s fast track designation. Anticancer mabs comprised the majority (64%) of the US orphan drug designated candidates, but not quite half (47%) of the fast track mabs in clinical study. Contact Details: Contact Person: Janice M. Reichert, Ph.D. Senior Research Fellow, Tufts Center for the Study of Drug Development, Boston, MA, USA Tel: [email protected] Business Opportunities mabs have proven to be successful on the market a number of the currently marketed mabs have global sales over US$1 billion. Pharmaceutical firms are now actively investing in programs dedicated to research and development (R&D) of mab drugs. In fact, a number of companies that focus on mab R&D have been acquired by large pharmaceutical firms, for example, Merck acquired Abmaxis, GlaxoSmithKline acquired Domantis, and Eisai acquired Morphotek. There have also been many collaborations and partnering deals between pharmaceutical and biotechnology firms in the mab R&D area, for example, Wyeth has partnered with Ablynx, Takeda has an agreement with Xoma, and Boehringer Ingelheim is in collaboration with Xencor. The focus of the business deals is the development of next-generation mabs with improved clinical safety and efficacy. mabs are complex molecules, yet their structure and functions are well-understood. This has allowed companies to rationally design new types of mab drugs, including smaller versions (single-chain or domain antibodies), mabs with more stable structures, and mabs that might interact with the immune system more efficiently. In addition, new targets and pathways important to the biology of cancer, immunological, and infective diseases are being discovered. The new knowledge might provide opportunities for the development of mabs with novel modes of action. Thus, mabs continue to have a great deal of potential as treatments for a variety of diseases. Fig 1: Therapeutic categories for monoclonal antibodies in clinical study.* *MAbs entered clinical study during January 1990 to March % anti-infective 10% other 56% cancer 24% immunological APBN Vol. 11 No

5 Table 1. Marketed Monoclonal Antibody Products. Generic name Trade name Indication first approved Year (country) of first approval Muromonab-CD3 Orthoclone Okt3 Reversal of kidney transplant 1986 (US) rejection Abciximab Reopro Prevention of blood 1994 (Sweden) clots in angioplasty Rituximab Rituxan Non-Hodgkin s lymphoma 1997 (US) Daclizumab Zenapax Prevention of kidney transplant rejection 1997 (US) Basiliximab Simulect Prevention of kidney transplant rejection 1998 (US) Palivizumab Synagis Prevention of respiratory syncytial 1998 (US) Infliximab Remicade Crohn s disease 1998 (US) Trastuzumab Herceptin Breast cancer 1998 (US) Gemtuzumab Mylotarg Acute myeloid leukemia 2000 (US) ozogamicin Alemtuzumab Campath-1H Chronic lymphocytic leukemia 2001 (US) Ibritumomab tiuxetan Zevalin Non-Hodgkin s lymphoma 2002 (US) Adalimumab Humira Rheumatoid arthritis 2002 (US) Omalizumab Xolair Asthma 2003 (US) Tositumomab-I131 Bexxar Non-Hodgkin s lymphoma 2003 (US) Efalizumab Raptiva Psoriasis 2003 (US) Cetuximab Erbitux Colorectal cancer 2003 (Switzerland) ch-tnt-i131 Advanced lung cancer 2003 (China) Bevacizumab Avastin Colorectal cancer 2004 (US) Natalizumab Tysabri Multiple sclerosis 2004 (US) Tocilizumab Actemra Castleman s disease 2005 (Japan) Nimotuzumab TheraCIM Advanced head/neck epithelial cancer 2005 (China) Ranibizumab Lucentis Macular degeneration 2006 (US) Panitumumab Vectibix Colorectal cancer 2006 (US) Eculizumab Soliris Paroxysmal nocturnal hemoglobinuria 2007 (US) 412 APBN Vol. 11 No